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I think Vascepa has 11yrs (10+1) of patent life remaining in the EU. That is now AMRN's most valuable asset besides cash. TEVA which sells brand and generics might have an interest in the obtaining the brand Vascepa and the already built in manufacturing supply. AMRN needs to hold a cc to discuss the various possibilities. CEO's position has been permanently damaged and will now be lot more willing to make a discounted deal before getting the boot.
Dew agree its a long shot but note how helpful the FDA was to P2 MDD drugs in 2019. Besides accepting as pivotal 05's 80 patient 5 site P2 as pivotal the FDA also did the same for SAGE-217 89 patient 14 day P2. As you know there's already a bunch of drugs approved for MDD. If the FDA is trying to jumpstart more MDD drugs then you'd think 05 as the 1st oral TRD drug might also get special treatment if it gets strong data from the upcoming P3.
Would the FDA consider a AXS-05 NDA for both MDD & TRD? AXSM has the 2 sig stat pivotals needed to submit a NDA for MDD indication. But they'll also have TLR for P3 TRD in March. I'm curious if its possible the FDA accepts a NDA that includes both indications? AXSM would have just 1 P3 for TRD but the patient populations for TRD and MDD are similar. The FDA surprised me a year ago by assigning pivotal status to 05's P2 MDD despite it had only 80 patients. The ongoing P3 TRD has >350 patients. The FDA also has given 05 a BTD for MDD and a Fast Track for TRD.
NEW YORK, Jan. 22, 2020 (GLOBE NEWSWIRE) -- Axsome Therapeutics, Inc. (AXSM), a clinical-stage biopharmaceutical company developing novel therapies for the management of central nervous system (CNS) disorders, today announced the completion of patient randomization in the STRIDE-1 study, a Phase 3, randomized, double-blind, active-controlled trial of AXS-05 in patients with treatment resistant depression (TRD). AXS-05 (dextromethorphan/bupropion modulated delivery tablet) is a novel, oral, investigational NMDA receptor antagonist with multimodal activity. Axsome remains on track to report topline results from STRIDE-1 in the first quarter of 2020.
About the STRIDE-1 Trial
STRIDE-1 (Symptom Treatment in Resistant Depression 1) is a Phase 3, randomized, double-blind, active controlled trial to assess the efficacy and safety of AXS-05 in the treatment of treatment resistant depression (TRD). Patients with major depressive disorder (MDD) who have previously failed one or two antidepressant treatments are treated in an open-label fashion with bupropion during a 6-week lead-in period. Patients who fail to respond to bupropion during this lead-in period are randomized in a 1:1 ratio to treatment with bupropion or AXS-05 in a double-blind fashion for 6 weeks. The primary endpoint is the change in the Montgomery-Åsberg Depression Rating Scale (MADRS) after 6 weeks of treatment.
About Treatment Resistant Depression (TRD)
Patients diagnosed with major depressive disorder (MDD) are defined as having TRD if they have failed two or more antidepressant therapies. MDD is a serious condition characterized by depressed mood or a loss of interest or pleasure in daily activities consistently for at least a two-week period, and which impairs social, occupational, educational, or other important functioning. According to the National Institute of Health, an estimated 7.1% of U.S. adults experience MDD each year. Nearly two-thirds of diagnosed and treated patients do not experience adequate treatment response with first-line therapy, and the majority of these initial failures also fail second-line treatment.
ITCI had a big price jump today but its sp could go up considerably more if the FDA accepts a sNDA for BPD. Luma reported sig stat P3 in mid 2019. BPD could be a larger indication then schizo because it has less atypical competition. Luma also looked good against BPD2 where most atypicals fail. Luma did have a failed BPD P3 but Luma scored exceptionally well (20 pts on MADRS) only to see a freaky large placebo effect keeping sig stat away. The FDA liked Luma for Schizo in 2019 so I expect they will also like Luma for BPD in 2020.
Both ACAD & NERV's drugs show a modest effect with good safety. Another to consider in that line is ITCI. I did not like Luma's last Schizo P3 fail but I've recently changed my mind with the 2 P3s for BPD. One was sig stat and the other failed but the placebo effect was the highest I've seen in a P3 BPD which provides a fair excuse. ITCI could be set up to get a 2 for 1 If Luma gets approved for the schizo indication in 4Q. ITCI could then follow up with a 2020 BPD sNDA with the 1 successful BPD P3. The FDA has asked for more data on the metabolites seen in dogs only. Imo the FDA would not be allowing the approx 1000 patients in the longterm schizo and BPD trials to continue to receive Luma if there was a serious concern. To me it looks like the FDA is considering approving Luma due to a strong safety profile which stands out vs other schizo drugs. The FDA may now want a last minute metabolite safety verification before approving Luma. If ITCI jumps that hurdle then they might own the only FDA approved Schizo/BPD atypical without a black box warning.
MIN-101's P2 was sig stat with both the 32 &64mg doses. Was also sig stat on many other tests. Good safety data except the 64mg arm had a QTc issue. That appears to have been solved with a delayed gastro release formulation. No FDA approved drug yet for neg schizo in US. Pharma not willing to test their drug in difficult Schizo Neg Symptoms indication vs placebo. Allergan tried sNDA for Vraylar because it beat a Risperdal arm for a neg symptoms. But the FDA refused because it wants to see a drug tested in a moderate positive schizo pop with high neg sym tested against a placebo arm which is what NERV did with its P2. NERV will have 101 P3 results in 4Q19. ACAD's pima is similar to 101 in that both are selective for the 5HT2A receptor. Pima just failed its P3 but drug was used as adj therapy for schizo & it was not a focused neg symptoms pop. But it should be noted pima was still able to get sig stat on a 2nd endpoint that just happens to be 101's P3 PE.
I just picked up 3 months of Vascepa. My insurance is Humana and presently Vascepa is a tier 4 drug. Its the only drug I take. Bit of a rip off but I chose to pay the $300 co-pay ($100/month). No prior auth required despite my trigs are hanging around 120 which is well below the 500 level.
Most SSRIs take about 6 weeks for a response. Remission rates bounce around widely but usually falls between 20-50%. Effexor a SNRI has shown better remission rates then most of the other antidepressants but it still falls well below SAGE-217's 64% remission rate.
Treatment of major depression: is improvement enough?
Ferrier IN1.
Author information
Abstract
The goals of antidepressant treatment are to induce remission and prevent relapse or recurrence. While response is the standard criterion applied to comparisons of antidepressant drugs indicating an improvement from baseline, the more stringent criterion of remission is more relevant to clinical practice because it indicates that the patient is asymptomatic (i.e., "well"). Patients may enter into a remission or partial remission, which is characterized by the presence of residual symptoms and an increased risk of relapse, impairment, and suicide. Studies with many antidepressants demonstrate response rates of 50% to 60% but remission rates of only 20% to 30%. Venlafaxine is an antidepressant that is characterized as a serotonin-norepinephrine reuptake inhibitor (SNRI). Using the criterion of remission, placebo-controlled and comparative trials demonstrate a higher remission rate with venlafaxine than with other antidepressants, thus improving the proportion of patients who are "well." Selection of optimal antidepressant therapy should consider drugs that have the greatest potential to induce remission.
Yes many of the popular MDD drugs have seen their sales crash due to generics. But SAGE-217 is the 1st in a different class of antidepressant that stands out for its fast acting effect and the unusually high remission rate obtained. Below is the 89 patient P3 MDD result.
Effect on Depressive Symptoms through end of Treatment (Day 15):
-Treatment with SAGE-217 was associated with a statistically significant mean reduction from baseline in the Hamilton Rating Scale for Depression (HAM-D) total score at Day 15 of 17.6 points compared with a 10.7 point mean reduction associated with placebo (p<0.0001).
-The majority of patients (64%) who received SAGE-217 achieved remission at Day 15 as determined by a HAM-D total score less than or equal to 7 (compared with 23% of patients who received placebo, p=0.0005).
-Other secondary endpoints (e.g., MADRS, CGI-I) were similarly highly significant at Day 15 (p≤0.002).
This study compares Lovaza+Statin to Statin and the #s compare poorly to REDUCE-IT.
https://www.mdedge.com/sites/default/files/Document/October-2018/fdp03510026.pdf
I would have preferred seeing the 64mg arm coming out on top on the BACS but any improvement on a cognitive scale is a rarity and nice to see the 32mg do well. The part of the paper I liked best was MIN-101 had a clinical meaningful effect in about 40% of patients.
"Cohen described a 0.5 SD effect size as “visible to the naked eye.” Given the distributional properties of change in this study, about 40% of participants demonstrate an improvement of 0.5 or greater, suggesting that a substantial minority of participants experienced benefit that was clinically meaningful."
Note the BACS is not being used as a primary or secondary endpoint in the ongoing 500 patient P3 neg symptoms in Schizo trial. As an aside the author of the paper happens to also be the inventor of BACS.
Its true Lumateperone has a much better safety profile compared to the current antipsychotics used in schizophrenia. But thats also true for a placebo pill. ITCI is trying to convince the FDA to accept combined data for the successful P2 & P3 trials along with the failed P3. Besides getting beat by the placebo arm another problem for the drug imo is there was no dose effect seen in the P2 or the last P3. An unusually high placebo effect should not cause the low dose to beat the hi dose. It appears to me the ITCI drug has a very weak effect at best. I am not shorting ITCI. I've never shorted a stock. I have briefly owned the stock in the past.
ITCI claimes the latest P3 fail occurred because of an unusually strong placebo effect that beat both the hi and low dose arms of its drug. But the risperidone arm easily beat the placebo effect which greatly hurts that argument imo. In fact all 3 of the other arms in that trial beat the dose ITCI hopes the FDA will approve. I'd be very surprised if the FDA does approve it.
Results for the P3 696 schizo patients tx for 6 wks with primary endpoint being change from baseline on the PANSS total score are below.
ITI-007 Low dose -15 points
ITI-007 High dose -14.6 pts
Placebo arm -15.1 pts
Risperidone -20.5 pts
SAGE's ceo has stated several times he wants nothing to do with a Big Pharma partner or a buyout. Jonas recently sold 223,000 SAGE shares so that alone screams to me no buyout. The proceeds from this offering will allow SAGE to run the P3s for 217 in MDD and later launch without BP's help.
http://investor.sagerx.com/static-files/6e4f452f-08b4-4dc2-8589-ff6a5d7fc130
Servier presented a related ampakine S47445 at CTAD. http://www.alzforum.org/news/conference-coverage/least-we-know-these-dont-work-negative-trials-ctad
"This drug is a positive allosteric modulator of AMPA glutamate receptors. The French company Servier has been evaluating it for people with Alzheimer’s disease who also have symptoms of depression (see Therapeutics database). At CTAD, Maria Pueyo told the audience that Servier decided to end its work with this drug in Alzheimer’s. That’s because its latest, six-month, Phase 2 trial of 520 people with mild to moderate Alzheimer’s showed no significant differences between the drug and placebo groups on the primary outcome, the ADAS-cog, or on secondary measures of daily function or depression for either of the three doses used.
“Safety was good but we had no efficacy on cognition or function,” Pueyo said. The drug did get into the CSF and increased glutamate in the brain, Pueyo said in response to audience questions, but still achieved none of the desired benefit. Curiously, symptoms of depression improved in both drug and placebo groups, perhaps as a consequence of receiving the added care and attention that come with participating in a clinical trial."
SAGE has run several PPD & MDD trials with 547 and the oral 217 with all showing outstanding reductions in the HAM-D. Marinus has nothing to show. SAGE's oral 217 is a 30mg QD tx while MRNS 's oral Ganaxolone is a 900mg BID dose. SAGE has decided to enlarge the P2 for 217 in PPD so it could qualify as a registration trial. So if Marinus ever gets good numbers for its IV in PPD it won't help because SAGE would then advance its oral 217 towards PPD which immediately kills off both Brexanolone and Ganaxolone because of their higher cost & IV inconvenience. In other words Marinus can't win even if its IV drug works great in PPD.
SAGE's 547 results was exceptional in the P2 PPD trial and so was the oral 217 in MDD with its unusually high 61.5% remission rate on the HAM-D within 15 days. MRNS has tested their drug in more trials then SAGE but none have come close to matching SAGE's results. Ganaxolone is similar to Brexanolone but the drugs get very different results. Possible reason why is on slide 30. http://files.shareholder.com/downloads/AMDA-2RFZJS/3196778368x0x921019/B0716953-8EB2-4D5D-8B6A-E4A1D61969E5/Sage_RD_Day_2016_Final.pdf
Incyte has an agreement with LLY that prevents it from using an oral tab for Alopecia areata or for Vitiligo so it is testing a 1.5% cream for both with some success. Jakafi's pricetag is >$100,000 per yr. Lilly probably doesn't want to see a cheaper oral derma version on the market. Link shows impressive results for oral ruxolitinib in small AA trial. http://insight.jci.org/articles/view/89790/figure/2
The best Alopecia Areata trial result was obtained with oral Ruxolitinib. ACRS appears to be far behind INCY which is running a P2 topical ruxolitinib and CNCE which has a P2 with a oral deuterated ruxolitinib. http://www.investorvillage.com/smbd.asp?mb=18114&mn=596&pt=msg&mid=16391346
Imo NERV is jumping because of the schizo negative symptoms play and not the depression.
http://www.xconomy.com/boston/2016/05/26/minervas-shares-soar-on-early-data-for-schizophrenia-drug/
ghmm if you are interested in CNCE then the JAMA paper is a must read imo.
http://jama.jamanetwork.com/article.aspx?articleid=2442936
I am a lot more impressed with 786 then you. I think it is the most promising of any Alz +Agitation drug and it stands out as being one of the few contenders that is not black boxed for mortality in the elderly. Incyte has a deal with LLY which prevents an oral Jakafi treatment for Alopecia Areata so currently testing a topical treatment and CNCE is going after AA with oral. Several JAKS have been able to produce full hair regrowth for a few patients who also had AA. There is a SA article out today you might want to read:
http://seekingalpha.com/article/3972263-concert-pharmaceuticals-jump-back-healthcare-specialty-pharma-powerhouse
CNCE has licensed DM/Q to Otsuka who has since taken the drug into P3s for alz+agitation and P2s for schizo and depression. CNCE tried to produce a once nightly dose of their deuterated Xyrem but their version caused morning drowsiness. CNCE's main drug is a deuterated version of Kalydeco. Advantage being their drug is dosed QD vs BID and won't need to be taken with a hi fat meal. Drug is about to start a P2 and CNCE has talked of plans to get drug approved as a stand alone therapy and partner it out to Bps who have their own corrector. Novartis might be interested in the drug since their P2 potentiator just flopped. CNCE just announced a new target of using an oral deuterated version of Jakafi to treat alopecia areata. Stock's price dropped on the announcement.
If Inter Partes Review is overturned by the supreme court do you think it will have much of an effect on settling legal drug patent issues? Should a MNTA or bio shareholder care about the decision either way? I'm not a lawyer but was thinking if IPR can reduce lawsuits then its generally good for bios. But I don't know so interested in other opinions. Sounds like the supreme court decides next month.
http://www.ipwatchdog.com/2016/04/24/cuozzo-supreme-court-value-inter-partes-reviews/id=68552/
VRTX has walled off the CF competition by having the only potentiator on the market. But Kalydeco may soon be facing better potentiators from CNCE and GLPG who each has one in a P2. GLPG has 2 correctors lined up to combo their potentiator with while CNCE is seeking to partner their deuterated Ivacaftor with a partner who has their own correctors. If you think those potentiators will fall short then VRTX should do very well because Kalydeco will eventually combo up with better correctors. VRTX's 1st combo attempt of lumacaftor/Ivacaftor has been a disappointment because it has shown only a small improvement over Kalydeco treatment alone.
It was nice to see the once a day dosing ability and a lowering of the male dosing concerns. Add in the better efficacy numbers and this drug should bury Xeljanz.
If you liked AVNR then take a look at CNCE. Otsuka bought out AVNR and decided to go with the CNCE deuterated AVP-786 for their two P3s in Alz behavior and also testing the drug in a P2 for MDD. CNCE will derive royalty and milestones if the drug succeeds. The P2 for the QDM drug had very good results so I expect to see good P3 numbers. CNCE also has a P1 deuterated version of VRTX's Kalydeco which is expected to become a multi-billion Cystic Fibrosis drug.
D-Xyrem proved to be too difficult a target to get QD dosing without AM drowsiness. JAZZ has to have that because Flamel's QD drug is advancing. GLPG is in charge of developing the CF drugs thru P2. GLPG's plan is to combine 2 correctors with 1 potentiator for the 508del indication but that is a bit ambitious since none has passed a P1 yet.
http://www.glpg.com/index.php/randd/alliances/cystic-fibrosis/
GLPG might be interested in CNCE's deuterated Ivacaftor as a shortcut. It is a QD version which may be an advantage over the BID Kalydeco. Tung the ceo of CNCE was responsible for developing Kalydeco when he previously worked at VRTX. He started a P1 for d-1va after CNCE issued a d-corrector patent in 2014. GLPG has 5 correctors in its pipeline and I thought the FDA panel today was clearly not impressed by VRTX's corrector (Lumacaftor) effectiveness.
Imo ITCI ceo sounds silly when she says ITI-007 had a cognitive effect in elderly dementia patients. She forgot to mention just 5 patients were on the drug and for only 7 days.
"eight patients with dementia were randomized to receive 9 mg ITI-007 (N=5) or placebo (N=3) orally once a day in the evening for seven days. The primary objectives of the study were to evaluate the safety, tolerability and pharmacokinetics of ITI-007 in the elderly and in the target dementia patient population. Secondary measures were included to explore the effects of ITI-007 on cognition and agitation."
Iwfal CNCE unlike CCXI failed its P2 diabetic nephropathy primary but did find some biomarker effects. Curious if you find any of these biomarker changes pertinent?
Abstract: [FR-PO899] Effect of CTP-499 on Biomarkers Associated with Chronic Kidney Disease in Patients with Type 2 Diabetes
Ara Aslanian, PhD, Kristine Hogan, Philip B. Graham, PhD, LuAnn A. Sabounjian, Lijun Wu, PhD. Concert Pharmaceuticals, Lexington, MA, United States.
Background:
The progression of CKD is intimately related to the pathophysiology of tubulointerstitial damage, as the severity of tubule injury predicts long-term clinical outcomes. Tubule cell dysfunction is mediated by pro-fibrotic and pro-inflammatory factors, thus therapeutic intervention that ameliorates these processes may be beneficial. CTP-499 is a novel, deuterium-containing, multi-subtype selective PDE inhibitor that had protective effects on renal function in patients with type 2 diabetic kidney disease in a 48-week Phase 2 clinical study. We have shown in non-clinical studies that CTP-499 has anti-fibrotic and anti-inflammatory activities consistent with inhibition of specific PDE subtypes. To investigate the mechanism of CTP-499 in diabetes-induced CKD, we examined a panel of biomarkers from this Phase 2 clinical trial patient population.
Methods: Results:
At 48 weeks, biomarkers associated with the severity of tubulointerstitial damage were significantly reduced in patients receiving CTP-499 compared to placebo, including IL-18 and clusterin (25% and 42%, respectively, P < 0.05; N = 65 CTP-499, 57-58 Placebo). In general, treatment-dependent changes were more prominent in patients with a baseline UACR = 850 mg/g, a group that shows more rapid decline in renal function than patients with lower baseline UACR. In this subgroup, the tubule injury markers MCP-1 and N-OPN were reduced by 34% and 55%, respectively (P < 0.05, N = 32 CTP-499, 27 Placebo) in addition to IL-18 and clusterin. Also, the extracellular matrix proteins fibronectin, collagen IV, and laminin, which undergo increased deposition in CKD, were significantly reduced in CTP-499-treated patients compared to placebo (13-68%; P < 0.05, N=65 CTP-499, 57-58 Placebo). These data are consistent with results showing that CTP-499 reduced tubule cell apoptosis and collagen deposition in the rat UUO kidney fibrosis model.
Conclusions:
Collectively, these data suggest CTP-499 has protective effects on renal tubules in diabetic kidney disease, and that anti-fibrotic mechanisms may contribute to this activity. These results further support continued development of this novel agent for the treatment of CKD.
Course: Annual Meeting: Abstract Sessions
Session: CKD: Epidemiology and Outcomes - II
Date/Time: Friday, November 14, 2014
CITI on AMRN
16 September 2014
Continuing REDUCE-IT Will Burn Cash Runway
? Conclusion(s) — We believe AMRN’s announcement on the plans to complete the REDUCE-IT outcomes study could weigh on shares in the near-term. In our note last week (AMRN: FDA’s Denial Expected; Reaction Overdone) we outlined the continuation of REDUCE-IT trial absent of the expanded Vascepa label for the ANCHOR indication as a negative development as it could elevate a financing overhang for AMRN shares. Management said spending on REDUCE-IT trial will be ~$30M-$40M/year with an interim analysis during 2016, and final results in early 2018. We rate AMRN Neutral with a $1.75 TP, and will await management financial guidance during the 3Q:14 earnings call to assess any potential impacts to our estimates.
? Continuing REDUCE-IT Isn’t Cheap — The REDUCE-IT trial (n=8000) is expected to cost $30M-$40M/year with a most likely readout of the results in early 2018. A pre-specified interim analysis after 60% of total events (CV-related events) is expected in 2016, and results from the final analysis of 100% of events is expected in early 2018. We therefore estimate ~$50M-$80M in costs until the interim analysis (depending when in `16), or ~90M-120M in costs until the expected final result is available. AMRN reported $151M in cash and equivalents at the end of Q2, and the company expects cash outflows for 2014 to be < $80M. The cash runway will depend on the ramp and revenues of the ongoing launch of Vascepa in the currently approved setting. We await financial guidance during the 3Q:14 earnings call to gain a clearer picture of the potential financing needs.
?Expansion of Label to Include ANCHOR Indication Remains Unlikely — AMRN’s announcement that they are committed to finishing the REDUCE-IT trial comes after the FDA rejected of AMRN’s appeal of the rescission of the ANCHOR SPA agreement for the 3rd time last week. The FDA has not yet decided on the application for label expansion of Vascepa regarding the ANCHOR indication itself, though the company continues to characterize the chances for the expanded label as “an uphill battle” and we view the chances for a positive outcome as very low.
AVP-923 is basically Mucinex DM. Both are supplying 30 mg of a slow release DM with a relatively inert ingredient. AVNR's problem is it needs to persuade insurances to pay 100 x more for AVP923 than it would for the generic otc cough med. A possible problem is bid dosing in memory impaired patients who might also buy the otc med when they come down with the flu. That would double their dose of prescribed DM. http://www.walmart.com/ip/Mucinex-DM-600-Mg-Guaifenesin-30-Mg-Dextromethorphan-Hbr-Extended-Release-Bi-Layer-Tablets-Expectorant-Cough-Suppressant-20-Ct/3514429
Anyone knows what this equates to in trigs?
Baseline Triacylglycerols Placebo arm=1.93 and at end 1.93 Absolute (mmolL)
Baseline Triacylglycerols Fenofibrate=1.99 reduced to 1.52
link to paper
d’Emden MC. Diabetologia. 2014;doi:10.1007/s00125-014-3344-3
Discussion
On the basis of ACCORD Lipid study results], the Food and Drug Administration reviewed the cardiovascular safety of fenofibrate in women with diabetes. Our results indicate that fenofibrate is generally safe for women with type 2 diabetes. Although in the FIELD study, the primary endpoint of non-fatal MI plus coronary death was not significantly reduced, the secondary endpoint of total CVD events was reduced (without adjustment for multiple comparisons). Women allocated fenofibrate, including those with dyslipidaemia at baseline, had risk reductions in CVD events that did not differ statistically significantly from those in men, and for some event types tended to have greater benefit. Women also had significantly greater improvements in tradi- tional lipids variables and in apolipoprotein B levels.
Differences between treatment groups in LDL-cholesterol concentrations always remained larger in women, and were most clearly evident in statin-naive patients. These differences were not explained by differences in baseline characteristics such as body habitus, insulin or metformin therapy, meno- pausal status or oestrogen use. The apparent attenuation over time of the effect of fenofibrate on lipid and apolipoprotein levels in both sexes combined was driven by the higher rate of statin initiation in the placebo groups than in those allocated to fenofibrate.
The significant differences between women and men in the effects of fenofibrate on lipid and apolipoproteins were unex- pected. Women were lighter than men, with a smaller body surface area, but had a higher body mass index. Sex differences in mass, BMI and body surface area might be associated with differences in the vol- ume of distribution or other pharmacodynamic properties of fenofibrate. Oestrogenic hormones are potential confounding factors, given that they are known to increase HDL- cholesterol and reduce LDL-cholesterol and to influence lipoprotein-related enzyme levels. In our study, most women (94%) were postmenopausal (average age at study entry 61 years), but the effects of fenofibrate in premenopausal and postmenopausal women were not different for lipoprotein measures or for clinical CVD event reductions, and too few women continued exogenous oestrogen therapy to have any plausible impact on the results. Nor did insulin use or differ- ences in statin uptake between the sexes explain the difference in LDL-cholesterol and fenofibrate response. Uptake of statin therapy during the trial may have confounded the treatment effects. We adjusted the results for statin uptake (and covariates), which is considered a better method of accounting for this than using analytical methods that do not maintain the randomised comparisons. In fact, there was little difference between the unadjusted results and the results adjusted for statin use and covariates. Metformin use, which can improve the lipid profile, was more common in women, but in FIELD, metformin use did not contribute materially to the observed sex differences in lipid and apolipoprotein changes.
Previous studies with fenofibrate or, indeed, any fibrate have not reported a sex difference in responsiveness to thera- py. However, most of the large prospective CVD intervention studies with fibrate monotherapy have either not included women or have had relatively small numbers of women [5, 6], and even fewer have had women with diabetes.
The ACCORD Lipid study had 1,694 women (31% of patients) randomly assigned to fenofibrate or placebo on background statin therapy [8]. Lipid changes by sex in ACCORD Lipid have yet to be published in a journal article, but have been reported to the US Food and Drug Administration and show larger LDL-cholesterol reduc- tions in women. In contrast to our study, ACCORD Lipid reported that the primary outcome (CVD death or non-fatal MI or non-fatal stroke) was less frequent (11.2%) in men using the combination of fenofibrate and simvastatin than in men receiving simvastatin alone (13.3%), but the rate for women was non-significantly more frequent in the combination therapy group (9.1% vs 6.6%); the difference between the sexes was significant ( p = 0.01 for interaction). Such sex- specific differences in treatment benefits were not apparent among participants with dyslipidaemia in ACCORD Lipid, where CVD benefits were greatest. FIELD has also reported similarly large CVD benefits in men and women with diabetes and dyslipidaemia. Only a small number of women in FIELD met the ACCORD Lipid definition for dyslipidaemia, but patterns of fenofibrate effect among them were similar to those for men
.
There are several potential reasons for the discrepant results between FIELD and ACCORD Lipid. All patients in ACCORD Lipid but fewer than one-third of FIELD patients received statin therapy. Patients in FIELD may have had a higher background risk by virtue of not being on statin therapy at randomisation, but they had a shorter duration of diabetes and a lower HbA1c at study entry. Nevertheless, CVD event rates among women in the control arm in FIELD appeared to be about 50% higher than in ACCORD Lipid. The apparent higher event rate combined with the greater number would offer substantially more pow- er in FIELD to evaluate the effects of fenofibrate in women. It is possible that the non-significantly adverse CVD result for women in ACCORD Lipid was just the play of chance. It is important to note that event rates were reduced similarly in dislipidaemic women and men in ACCORD Lipid [19]. The results do suggest that the combination of fenofibrate with a statin will be most beneficial for CVD prevention in patients with dyslipidaemia on statin therapy and are consistent with findings in FIELD that the effect is greatest in patients with dyslipidaemia.
Conclusion
In summary, the FIELD study showed that both men and women with diabetes had significantly improved lipoproteins with fenofibrate therapy, with changes in women being greater than in men. The primary endpoint of the study was not statistically significantly reduced, but total CVD events were significantly lowered with allocation to fenofibrate. In pre- specified analyses by sex, there was no evidence that women did worse than men and for several endpoints, including total CVD events, there was a trend suggesting that women may have benefited more. These benefits were particularly large in those with dyslipidaemia, consistent with the findings in ACCORD Lipid. These results suggest that fenofibrate is effective for improving an adverse lipoprotein profile and for reducing total CVD event risk in women with type 2 diabetes, especially those with dyslipidaemia.
Large trial shows fenofibrate lowers CV deaths in diabetic women by 30%. This could help get Vascepa's spa reinstated imo because diabetics usually have high trigs.
---
"The finding is good news for women," says the study's chairman, University of Sydney Professor, Tony Keech.
"The study shows that fenofibrate reduced the risk of dying from cardiovascular disease, or having a stroke or other adverse cardiovascular event by 30 per cent in women and 13 per cent in men."
The leading cause of death in women, cardiovascular disease (CVD) is a constellation of ailments affecting the heart and blood vessels, including conditions such as coronary heart disease, stroke, and diseases of the small blood vessels, such as in the eyes and kidneys.
Published in Diabetologia, the five-year study of nearly 10,000 people with type-2 diabetes also assessed fenofibrate's impact on a range of lipoproteins and triglycerides (circulating blood fats) that elevate the risk of cardiovascular events such as stroke and heart attack, and the need for medical procedures such as coronary artery bypass graft surgery.
Among type-2 diabetic patients with an elevated risk of cardiovascular disease – those with high levels of triglycerides and low levels of "good" cholesterol (high-density lipoprotein or HDL) – fenofibrate cut adverse cardiovascular outcomes by 30 per cent in women and 24 per cent in men.
A previous smaller US study had suggested that fenofibrate was not beneficial for women. This new study recommends that fenofibrate be considered as a useful way to reduce the risk of cardiovascular disease in both women and men with Type-2 diabetes.
High cholesterol is a serious health problem affecting one in three Australians. It is a leading risk factor for the deposition of circulating fats on the walls of blood vessels (atherosclerosis), which heightens the risk of heart attack and stroke.
Fenofibrate stimulates the action of an enzyme that breaks down triglycerides and low-density lipoproteins. Stimulating this enzyme increases the breakdown of triglycerides (another type of blood lipid) and low-density lipoproteins in the bloodstream and raises HDL cholesterol.
"Cardiovascular disease is the most common cause of death in women, almost three times more common than breast cancer," says the study's lead author, Associate Professor Michael d'Emden of the Royal Brisbane Hospital.
"Its symptoms are sometimes harder to diagnose in women and often the typical chest pain of a heart attack does not occur in people with diabetes.
"Therefore, better awareness among patients and their GPs is vital. Predominant symptoms include breathlessness, sweating, nausea, fatigue or arm pain."
http://medicalxpress.com/news/2014-08-cholesterol-drug-heart-percent-diabetic.html
Curious if you have discussed Pimavanserin with Hargreaves. ACAD is about to start it in a P2 PD sleep trial. Doubt we ever see it in a P3 because a successful P2 may be enough to capture AD/PD sleep rxs away from patients currently using off label low dose Desyrel and Seroquel. What do you think?
ESC Conf starts Aug 30th-EPA Abstracts
Pre-treatment with pure eicosapentaenoic acid in addition to statins can reduce the index of microcirculatory resistance after percutaneous coronary intervention Akiyoshi KURITA (Nagakute, JP)
Effect of pitavastatin and eicosapentaenoic acid on coronary artery calcification detected by multi detector-row computed tomography. Kazufumi NAKAMURA (Okayama, JP)
Eicosapentaenoic acid treatment reduces acute inflammatory response and ventricular arrhythmias in patients with reperfused acute myocardial infarction Saori TSUKUDA (Takamatsu City, JP)
Clinical outcomes of early initiation of pure eicosapentaenoic acid supplement after percutaneous coronary intervention in patients with acute coronary syndrome. Fumi YOKOHAMA (Takamatsu, JP)
Association between plaque vulnerability and eicosapentaenoic acid to arachidonic acid in non-hypercholesterolemia patients Maoto HABARA (Toyohashi, JP)
Combined administration of eicosapentaenoic acid and docosahexaenoic acid reduces atherosclerotic lesion in apolipoprotein E-deficient mice Akira TAKASHIMA (Tokushima, JP)
Eicosapentaenoic acid to arachidonic acid ratio is associated with the presence of thin-cap fibroatheroma determined by optical coherence tomography Yasushi WAKABAYASHI (Saitama, JP)
Inhibitory effects of eicosapentaenoic acid on arterial calcification in klotho mutant mice, an animal model of typical aging Kazufumi NAKAMURA (Okayama, JP)
http://spo.escardio.org/default.aspx?eevtid=69
Master my poster boy candidate would be Hetlioz (tasimelteon) which is similar to Rozerem and assigned orphan status for Non-24 which affects totally blind people. Patients take 1 tablet a day and it will cost $250 or $7,500 per month. Vanda might have a problem convincing insurances to cover this one.
Doc's rational explanation for Niacin's poor effect.
http://www.pace-cme.org/d/562/hps2-thrive-and-the-future-of-clinical-endpoint-trials
"Toxic" Niaspan sold $900 million in US last year. This news could help Vascepa's sales.
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By Marilynn Marchione
AP Chief Medical Writer
Jul 16, 2014
New details from two studies reveal more side effects from niacin, a drug that hundreds of thousands of Americans take for cholesterol problems and general heart health. Some prominent doctors say the drug now seems too risky for routine use.
Niacin is a type of B vitamin long sold over the counter and in higher prescription doses. Some people take it alone or with statin medicines such as Lipitor for cholesterol problems.
Niacin users' main complaint has been flushing, so drug companies have been testing extended-release and combining other medicines with it to minimize that problem. Introduced in the 1950s, the drug hadn't been rigorously tested until recent years when makers of prescription versions were seeking market approval.
The two studies were testing prescription versions of niacin, and the bottom line — that it didn't help prevent heart problems any more than statins alone do — has already been announced. Some of the side effect information, including a troubling rise in deaths among niacin users in one study, also was known but many doctors have been waiting for full details and verification of the results before drawing firm conclusions about the drug's safety and effectiveness.
Those details are in this week's New England Journal of Medicine.
The larger study suggests that "for every 200 people that we treat with niacin, there is one excess death," plus higher rates of bleeding, infections and other problems — "a completely unacceptable level" of harm, said Dr. Donald Lloyd-Jones of Northwestern University in Chicago. "Niacin should not be used routinely in clinical practice at all."
He co-led a panel for the American Heart Association and American College of Cardiology that recently issued new cholesterol treatment guidelines. The group did not recommend niacin but said it could be considered for certain patients. If the panel had seen the new results, it "almost certainly" would have recommended against niacin's routine use, Lloyd-Jones said.
Heart specialists stress that patients never should stop taking any medicine without first talking with their doctors. Many have shied away from niacin since the initial results came out, but more than 700,000 prescriptions for various niacin drugs are written each month in the U.S. The top brand is Abbott Laboratories' Niaspan, which had nearly $900 million in sales in the U.S. alone last year, according to IMS Health, a health data firm.
The larger of the two studies tested Tredaptive — a Merck & Co. combo of niacin and an anti-flushing medicine — in nearly 26,000 people already taking a statin. Full results confirm there was a 9 percent increase in the risk of death for those taking the drug — a result of borderline statistical significance, meaning the difference could have occurred by chance alone, but still "of great concern," Lloyd-Jones wrote in a commentary in the medical journal.
The drug also brought higher rates of gastrointestinal and muscle problems, infections and bleeding. More diabetics on the drug lost control of their blood sugar, and there were more new cases of diabetes among niacin users.
The initial results in December 2012 led Merck to stop pursuing approval of Tredaptive in the U.S. and to tell doctors in dozens of countries where it was sold to stop prescribing it to new patients.
Prompted by that study, leaders of an earlier one that tested a different niacin drug, Niaspan, re-examined side effects among their 3,414 participants and detailed them in a letter in the medical journal.
Besides more gastrointestinal, blood-sugar and other complications, the new report details a higher rate of infections and a trend toward higher rates of serious bleeding.
The consistency of the results on studies testing multiple types of niacin "leaves little doubt that this drug provides little if any benefits and imposes serious side effects," said Yale University cardiologist Dr. Harlan Krumholz.
"It's an astonishing reversal of fortune" for niacin, one of the very earliest cholesterol treatments, he said. "This is a billion-dollar drug and it never really had the evidence to warrant that sort of blockbuster status."
The studies were on prescription niacin; risks and benefits of over-the-counter forms are unclear.
Lloyd-Jones said niacin still may be appropriate for some people with very high heart risks who cannot take statins, and for people with very high triglycerides that can't be controlled through other means.
Krumholz said patients should talk with doctors about other treatment options besides niacin.
"This drug can hurt you," he said.